Anti-fungal composition

ABSTRACT

An anti-fungal product for delivering at least two different anti-fungals that is comprised of three dosage forms with different release profiles with each anti-fungal being present in at least one of the dosage forms.

[0001] This invention relates to anti-fungal compositions and the usethereof. More particularly, this invention relates to a composition forthe delivery of two or more anti-fungals, and the use thereof.

[0002] In many cases, it is desirable to employ two differentanti-fungals in the treatment of a fungus infection, in that suchanti-fungals may have complementary mechanisms of action that facilitatetreatment of the fungus infection.

[0003] The present invention is directed to a new and improvedcomposition that delivers two or more anti-fungals, and the use thereof.

[0004] In accordance with an aspect of the present invention, there isprovided an anti-fungal product for delivering at least two differentanti-fungals that is comprised of at least three dosage forms eachcomprised of at least one anti-fungal agent and a pharmaceuticallyacceptable carrier, with one of the dosage forms including at least oneof the at least two anti-fungals and at least one dosage form includingat least a second anti-fungal of the at least two anti-fungals.

[0005] Thus, for example, each of the dosage forms may include two ormore anti-fungals, or one or two of the dosage forms may include onlyone of the two or more anti-fungals and each of the remaining dosageforms may include only one or more of the different anti-fungals or twoor more of the anti-fungals. Thus, in accordance with this aspect of theinvention, there is an anti-fungal product for delivering at least twodifferent anti-fungals wherein the product includes at least threedosage forms wherein each of the at least two anti-fungals is present inat least one of the three dosage forms.

[0006] In a preferred embodiment each of the dosage forms has adifferent release profile, with one of the dosage forms being animmediate release dosage form.

[0007] In another aspect, the present invention is directed to treatinga bacterial infection by administering to a host in need thereof ananti-fungal product as hereinabove and hereinafter described.

[0008] Thus, in accordance with an aspect of the present invention,there is provided a single or unitary anti-fungal product that hascontained therein at least three anti-fungal dosage forms, each of whichhas a different release profile, whereby the anti-fungal contained ineach of the at least three dosage forms is released at different times,and wherein at least one of the dosage forms includes at least a firstanti-fungal and at least one of the dosage forms includes at least asecond anti-fungal different from the first anti-fungal.

[0009] In accordance with a further aspect of the invention, theanti-fungal product may be comprised of at least four different dosageforms, each of which starts to release the anti-fungal contained thereinat different times after administration of the anti-fungal product.

[0010] The anti-fungal product generally does not include more than fivedosage forms with different release times.

[0011] In accordance with a preferred embodiment, the anti-fungalproduct has an overall release profile such that when administered themaximum serum concentration of the total anti-fungal released from theproduct is reached in less than twelve hours, preferably in less thaneleven hours. In an embodiment, the maximum serum concentration of thetotal anti-fungal released from the anti-fungal product is achieved noearlier than four hours after administration.

[0012] In accordance with one preferred embodiment of the invention, oneof the at least three dosage forms is an immediate release dosage formwhereby initiation of release of anti-fungal therefrom is notsubstantially delayed after administration of the anti-fungal product.The second and third of the at least three dosage forms is a delayeddosage form (which may be a pH sensitive or a non-pH sensitive delayeddosage form, depending on the type of anti-fungal product), wherebyanti-fungal released therefrom is delayed until after initiation ofrelease of anti-fungal from the immediate release dosage form. Moreparticularly, anti-fungal release from the second of the at least twodosage forms achieves a C_(max) (maximum serum concentration in theserum) at a time after anti-fungal released from the first of the atleast three dosage forms achieves a C_(max) in the serum, andanti-fungal released from the third dosage form achieves a C_(max) inthe serum after the C_(max) of anti-fungal released from the seconddosage form.

[0013] In one embodiment, the second of the at least two dosage formsinitiates release of anti-fungal contained therein at least one hourafter the first dosage form, with the initiation of the releasetherefrom generally occurring no more than six hours after initiation ofrelease of anti-fungal from the first dosage form of the at least threedosage forms.

[0014] In general, the immediate release dosage form produces a C_(max)for anti-fungal released therefrom within from about 0.5 to about 2hours, with the second dosage form of the at least three dosage formsproducing a C_(max) for anti-fungal released therefrom in no more thanabout four hours. In general, the C_(max) for such second dosage form isachieved no earlier than two hours after administration of theanti-fungal product; however, it is possible within the scope of theinvention to achieve C_(max) in a shorter period of time.

[0015] As hereinabove indicated, the anti-fungal product may contain atleast three or at least four or more different dosage forms. Forexample, the anti-fungal released from the third dosage form reaches aC_(max) at a time later than the C_(max) is achieved for anti-fungalreleased from each of the first and second dosage forms. In a preferredembodiment, release of anti-fungal from the third dosage form is startedafter initiation of release of anti-fungal from both the first dosageform and the second dosage form. In one embodiment, C_(max) foranti-fungal release from the third dosage form is achieved within eighthours.

[0016] In another embodiment, the anti-fungal product contains at leastfour dosage forms, with each of the at least four dosage forms havingdifferent release profiles, whereby anti-fungal released from each ofthe at least four different dosage forms achieves a C_(max) at adifferent time.

[0017] As hereinabove indicated, in a preferred embodiment, irrespectiveof whether the anti-fungal contains at least three or at least fourdifferent dosage forms each with a different release profile, C_(max)for all the anti-fungal released from the anti-fungal product isachieved in less than twelve hours, and more generally is achieved inless than eleven hours.

[0018] In a preferred embodiment, the anti-fungal product is a once aday product, whereby after administration of the anti-fungal product, nofurther product is administered during the day; i.e., the preferredregimen is that the product is administered only once over a twenty-fourhour period. Thus, in accordance with the present invention, there is asingle administration of an anti-fungal product with the anti-fungalbeing released in a manner such that overall anti-fungal release iseffected with different release profiles in a manner such that theoverall C_(max) for the anti-fungal product is reached in less thantwelve hours. The term single administration means that the totalanti-fungal administered over a twenty-four hour period is administeredat the same time, which can be a single tablet or capsule or two or morethereof, provided that they are administered at essentially the sametime.

[0019] Thus in accordance with an aspect of the invention, there isprovided a single dosage anti-fungal product comprised of at least threeanti-fungal dosage forms each having a different release profile witheach of the dosage forms including at least one of a first or secondanti-fungal and at least one of the three dosage forms including atleast the first anti-fungal and at least one of the dosage formsincluding at least the second anti-fungal. Each of the dosage forms ofanti-fungal in a pharmaceutically acceptable carrier may have one ormore anti-fungals.

[0020] It is to be understood that when it is disclosed herein that adosage form initiates release after another dosage form, suchterminology means that the dosage form is designed and is intended toproduce such later initiated release. It is known in the art, however,notwithstanding such design and intent, some “leakage” of anti-fungalmay occur. Such “leakage” is not “release” as used herein.

[0021] If at least four dosage forms are used, the fourth of the atleast four dosage form may be a sustained release dosage form or adelayed release dosage form. If the fourth dosage form is a sustainedrelease dosage form, even though C_(max) of the fourth dosage form ofthe at least four dosage forms is reached after the C_(max) of each ofthe other dosage forms is reached, anti-fungal release from such fourthdosage form may be initiated prior to or after release from the secondor third dosage form.

[0022] In accordance with an aspect of the present invention, there isprovided an anti-fungal composition that is a mixture of anti-fungalcompositions or dosage forms wherein said composition contains a firstcomposition or dosage form comprising a first anti-fungal and apharmaceutically acceptable carrier; a second composition or dosage formcomprising the first anti-fungal and a pharmaceutically acceptablecarrier; a third composition or dosage form comprising a secondanti-fungal different from the first anti-fungal and a pharmaceuticallyacceptable carrier; and a fourth composition or dosage form comprisingthe second anti-fungal and a pharmaceutically acceptable carrier;wherein the second and third compositions each have a release profilethat provides a maximum serum concentration of the first anti-fungalreleased from the second composition and a maximum serum concentrationfor the second anti-fungal released from the third composition at a timeafter the first anti-fungal released from the first composition reachesa maximum serum concentration, and wherein the fourth composition has arelease profile that provides for a maximum serum concentration of thesecond anti-fungal released from the fourth composition at a time afterthe anti-fungals released from the second and third compositions reach amaximum serum concentration.

[0023] In one embodiment, the release profiles of the second and thirdcomposition are such that the maximum serum concentration of the firstanti-fungal released from the second composition, and the maximum serumconcentration of the second anti-fungal released from the thirdcomposition are reached at approximately the same time, or where thefirst anti-fungal reaches a maximum serum concentration before or afterthe second anti-fungal reaches a maximum serum concentration.

[0024] In effect, in accordance with a preferred embodiment of thepresent invention, there is provided a first pulse in which a firstanti-fungal reaches a maximum serum concentration, a second pulsewherein a further dosage of the first anti-fungal, and an initial dosageof the second anti-fungal reach a maximum serum concentration at a timeafter the first pulse of the first anti-fungal reaches a maximum serumconcentration, and a third pulse wherein an additional dosage of thesecond anti-fungal reaches a maximum serum concentration at a time afterthe maximum serum concentration is reached for each of the first andsecond anti-fungal dosages provided in the second pulse.

[0025] In a preferred embodiment of the present invention, the firstdosage of the first anti-fungal achieves a maximum serum concentrationwithin four hours after administration of the anti-fungal composition;the second dosage of the first anti-fungal and the first dosage of thesecond anti-fungal each reach a maximum serum concentration within fourto eight hours after administration of the anti-fungal composition; andthe second dosage of the second anti-fungal reaches a maximum serumconcentration within twelve hours after administration of theanti-fungal composition.

[0026] Thus, in accordance with an aspect of the present invention,there is provided an anti-fungal composition that includes fourdifferent dosage forms, with the first dosage form providing an initialdosage of a first anti-fungal, the second dosage form providing afurther dosage of the first anti-fungal; the third dosage form providingan initial dosage of a second anti-fungal; and the fourth dosage formproviding an additional dosage of the second anti-fungal, wherein theanti-fungals released from the second and third dosage forms reach amaximum serum concentration at a time after the anti-fungal releasedfrom the first dosage form reaches a maximum serum concentration, andthe anti-fungal released from the fourth dosage form reaching a maximumserum concentration at a time after the times at which the anti-fungalsreleased from each of the first, second, and third dosage forms reach amaximum serum concentration.

[0027] In one embodiment of the invention, the first dosage formprovides for immediate release, the second and third dosage formsprovide for a delayed release (pH or non pH dependent, with the seconddosage form preferably being a pH dependent release), and the fourthdosage form provides for pH dependent or non pH dependent releasepreferably non pH dependent release.

[0028] In formulating the anti-fungal composition of the presentinvention, which contains four different dosage forms, as hereinabovedescribed, the first dosage form generally contains from about 30percent to about 80 percent of the first anti-fungal; the second dosageform contains from about 30 percent to about 80 percent of the firstanti-fungal; the third dosage form contains from about 30 percent toabout 80 percent of the second anti-fungal, and the fourth anti-fungaldosage form contains from about 30 percent to about 80 percent of thesecond anti-fungal. In formulating a composition comprised of such fourdosage forms or units, each unit or dosage form is present in an amountof at least 20 percent by weight, with each dosage form or unit beingpresent in the overall composition in an amount that generally does notexceed 60 percent by weight.

[0029] Each of the first and second dosage forms include from 20% to 80%of the total dosage of the first anti-fungal to be provided by thecomposition, and each of the first and second dosage forms may includethe same or different dosages of the first anti-fungal.

[0030] Each of the third and fourth dosage forms include from 20% to 80%of the total dosage of the second anti-fungal to be delivered by thecomposition, and each of the third and fourth units may have the same ordifferent dosages of the anti-fungal.

[0031] In formulating an anti-fungal product in accordance with theinvention, in one embodiment, the immediate release dosage form of theproduct generally provides from about 20% to about 50% of the totaldosage of anti-fungal to be delivered by the product, with suchimmediate release dosage form generally providing at least 25% of thetotal dosage of the anti-fungal to be delivered by the product. In manycases, the immediate release dosage form provides from about 20% toabout 30% of the total dosage of anti-fungal to be delivered by theproduct; however, in some cases it may be desirable to have theimmediate release dosage form provide for about 45% to about 50% of thetotal dosage of anti-fungal to be delivered by the product.

[0032] The remaining dosage forms deliver the remainder of theanti-fungal. If more than one delayed release dosage form is used, inone embodiment, each of the delayed release dosage forms may provideabout equal amounts of anti-fungal; however, they may also be formulatedso as to provide different amounts.

[0033] In one embodiment, where the composition contains one immediaterelease component and two delayed release components, the immediaterelease component provides from 20% to 35% (preferably 20% to 30%), byweight, of the total anti-fungal; where there is three delayed releasecomponents, the immediate release component provides from 15% to 30%, byweight, of the total anti-fungal; and where there are four delayedrelease components, the immediate release component provides from 10% to25%, by weight, of the total anti-fungal.

[0034] With respect to the delayed release components, where there aretwo delayed release components, the first delayed release component (theone released earlier in time) provides from 30% to 60%, by weight, ofthe total anti-fungal provided by the two delayed release componentswith the second delayed release component providing the remainder of theanti-fungal.

[0035] Where there are three delayed release components, the earliestreleased component provides 20% to 35% by weight of the totalanti-fungal provided by the three delayed release components, the nextin time delayed release component provides from 20% to 40%, by weight,of the anti-fungal provided by the three delayed release components andthe last in time providing the remainder of the anti-fungal provided bythe three delayed release components.

[0036] When there are four delayed release components, the earliestdelayed release component provides from 15% to 30%, by weight, the nextin time delayed release component provides from 15% to 30%, the next intime delayed release component provides from 20% to 35%, by weight, andthe last in time delayed release component provides from 20% to 35%, byweight, in each case of the total anti-fungal provided by the fourdelayed release components.

[0037] The overall composition includes each of the anti-fungals in atherapeutically effective amount. The specific amount(s) is dependant onthe anti-fungal used, the disease or infection to be treated, and thenumber of times of day that the composition is to be administered.

[0038] The anti-fungal composition of the present invention may beadministered for example, by any one of the following routes ofadministration: sublingual, transmucosal, transdermal, parenteral, oral,preferably by oral administration.

[0039] The anti-fungal product of the present invention, as hereinabovedescribed, may be formulated for administration by a variety of routesof administration. For example, the anti-fungal product may beformulated in a way that is suitable for topical administration;administration in the eye or the ear; rectal or vaginal administration;as nose drops; by inhalation; as an injectable; or for oraladministration. In a preferred embodiment, the anti-fungal product isformulated in a manner such that it is suitable for oral administration.

[0040] For example, in formulating the anti-fungal product for topicaladministration, such as by application to the skin, the at least twodifferent dosage forms, each of which contains an anti-fungal, may beformulated for topical administration by including such dosage forms inan oil-in-water emulsion, or a water-in-oil emulsion. In such aformulation, the immediate release dosage form is in the continuousphase, and the delayed release dosage form is in a discontinuous phase.The formulation may also be produced in a manner for delivery of threedosage forms as hereinabove described. For example, there may beprovided an oil-in-water-in-oil emulsion, with oil being a continuousphase that contains the immediate release component, water dispersed inthe oil containing a first delayed release dosage form, and oildispersed in the water containing a third delayed release dosage form.

[0041] It is also within the scope of the invention to provide ananti-fungal product in the form of a patch, which includes anti-fungaldosage forms having different release profiles, as hereinabovedescribed.

[0042] In addition, the anti-fungal product may be formulated for use inthe eye or ear or nose, for example, as a liquid emulsion. For example,the dosage form may be coated with a hydrophobic polymer whereby adosage form is in the oil phase of the emulsion, and a dosage form maybe coated with hydrophilic polymer, whereby a dosage form is in thewater phase of the emulsion.

[0043] Furthermore, the anti-fungal product with at least threedifferent dosage forms with different release profiles may be formulatedfor rectal or vaginal administration, as known in the art. This may takethe form of a cream or emulsion, or other dissolvable dosage formsimilar to those used for topical administration.

[0044] As a further embodiment, the anti-fungal product may beformulated for use in inhalation therapy by coating the particles andmicronizing the particles for inhalation.

[0045] In a preferred embodiment, the anti-fungal product is formulatedin a manner suitable for oral administration. Thus, for example, fororal administration, each of the dosage forms may be used as a pellet ora particle, with a pellet or particle then being formed into a unitarypharmaceutical product, for example, in a capsule, or embedded in atablet, or suspended in a liquid for oral administration.

[0046] Alternatively, in formulating an oral delivery system, each ofthe dosage forms of the product may be formulated as a tablet, with eachof the tablets being put into a capsule to produce a unitary anti-fungalproduct. Thus, for example, anti-fungal products may include a firstdosage form in the form of a tablet that is an immediate release tablet,and may also include two or more additional tablets, each of whichprovides for a delayed release of the anti-fungal, as hereinabovedescribed, whereby the C_(max) of the anti-fungal released from each ofthe tablets is reached at different times, with the C_(max) of the totalanti-fungal released from the anti-fungal product being achieved in lessthan twelve hours.

[0047] The formulation of an anti-fungal product including at leastthree dosage forms with different release profiles for different routesof administration is deemed to be within the skill of the art from theteachings herein. As known in the art, with respect to delayed release,the time of release can be controlled by the concentration ofanti-finals in the coating and/or the thickness of the coating.

[0048] The Immediate Release Component

[0049] The immediate release portion of this system can be a mixture ofingredients that breaks down quickly after administration to release theanti-fungal. This can take the form of either a discrete pellet orgranule that is mixed in with, or compressed with, the other threecomponents.

[0050] The materials to be added to the anti-finals for the immediaterelease component can be, but are not limited to, microcrystallinecellulose, corn starch, pregelatinized starch, potato starch, ricestarch, sodium carboxymethyl starch, hydroxypropylcellulose,ydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose,chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linkedchitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol,sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose,polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol,Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs(PEG2000-10000) and high molecular weight PEGs (Polyox) with molecularweights above 20,000 daltons.

[0051] It may be useful to have these materials present in the range of1.0 to 60% (W/W).

[0052] In addition, it may be useful to have other ingredients in thissystem to aid in the dissolution of the drug, or the breakdown of thecomponent after ingestion or administration. These ingredients can besurfactants, such as sodium lauryl sulfate, sodium monoglycerate,sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitanmonooleate, glyceryl monostearate, glyceryl monooleate, glycerylmonobutyrate, one of the non-ionic surfactants such as the Pluronic lineof surfactants, or any other material with surface active properties, orany combination of the above.

[0053] These materials may be present in the rate of 0.05-15% (W/W).

[0054] The Delayed Release Component

[0055] The components in this composition are the same immediate releaseunit, but with additional polymers integrated into the composition, oras coatings over the pellet or granule.

[0056] Materials that can be used to obtain a delay in release suitablefor this component of the invention can be, but are not limited to,polyethylene glycol (PEG) with molecular weight above 4,000 daltons(Carbowax, Polyox), waxes such as white wax or bees wax, paraffin,acrylic acid derivatives (Eudragit), propylene glycol, andethylcellulose.

[0057] Typically these materials can be present in the range of 0.5-25%(W/W) of this component.

[0058] The Enteric Release Component

[0059] The components in this composition are the same as the immediaterelease component, but with additional polymers integrated into thecomposition, or as coatings over the pellet or granule.

[0060] The kind of materials useful for this purpose can be, but are notlimited to, cellulose acetate pthalate, Eudragit L, and other pthalatesalts of cellulose derivatives.

[0061] These materials can be present in concentrations from 4-20%(W/W).

[0062] The following are representative examples of some antifungalsthat can be employed in the composition of the invention: amphotericinB, flucytosine, fluconazole, griseofulvin, miconazole nitrate,terbinafine hydrochloride, ketoconazole, itraconazole, undecylenic acidand chloroxylenol, ciclopirox, clotrimazole, butenafine hydrochloride,nystatin, naftifine hydrochloride, oxiconazole nitrate, seleniumsulfide, econazole nitrate, terconazole, butoconazole nitrate,carbol-fuchsin, clioquinol, methylrosaniline chloride, sodiumthiosulfate, sulconazole nitrate, terbinafine hydrochloride,tioconazole, tolnaftate, undecylenic acid and undecylenate salts(calcium undecylenate, copper undecylenate, zinc undecylenate)

[0063] The invention will be further described with respect to thefollowing examples; however, the scope of the invention is not limitedthereby. All percentages in this specification, unless otherwisespecified, are by weight.

[0064] Immediate Release Component

[0065] Formulate the composition by mixing the ingredients in a suitablepharmaceutical mixer or granulator such as a planetary mixer, high-sheargranulator, fluid bed granulator, or extruder, in the presence of wateror other solvent, or in a dry blend. If water or other solvent was used,dry the blend in a suitable pharmaceutical drier, such as a vacuum ovenor forced-air oven. The product may be sieved or granulated, andcompressed using a suitable tablet press, such as a rotary tablet press.Example 1: Fluconazole 65% (W/W) Microcrystalline cellulose 20 Povidone10 Croscarmellose sodium  5 Example 2: Fluconazole 55% (W/W)Microcrystalline cellulose 25 Povidone 10 Croscarmellose sodium 10Example 3: Fluconazole 65% (W/W) Microcrystalline cellulose 20Hydroxypropylcellulose 10 Croscarmellose sodium  5 Example 4:Fluconazole 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol2000 10 Hydroxypropylcellulose  5 Example 5: Fluconazole 75% (W/W)Polyethylene glycol 8000 20 Polyvinylpyrrolidone  5 Example 6:Ketoconazole 65% (W/W) Microcrystalline cellulose 20Hydroxypropylcellulose 10 Croscarmellose sodium  5 Example 7:Ketoconazole 75% (W/W) Microcrystalline cellulose 15Hydroxypropylcellulose  5 Croscarmellose sodium  5 Example 8:Ketoconazole 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol2000 10 Hydroxypropylcellulose  5 Example 9: Ketoconazole 75% (W/W)Polyethylene glycol 8000 20 Polyvinylpyrrolidone  5 Example 10:Griseofulvin 65% (W/W) Microcrystalline cellulose 20Hydroxypropylcellulose 10 Croscarmellose sodium  5 Example 11:Griseofulvin 75% (W/W) Microcrystalline cellulose 15Hydroxypropylcellulose  5 Croscarmellose sodium  5 Example 12:Griseofulvin 75% (W/W) Polyethylene glycol 4000 10 Polytheylene glycol2000 10 Hydroxypropylcellulose  5 Example 13: Cirpofloxacin 75% (W/W)Polyethylene glycol 8000 20 Polyvinylpyrrolidone  5 Example 14:Terbinafine HCl 75% (W/W) Polyethylene glycol 4000 10 Polyethyleneglycol 2000 10 Hydroxypropylcellulose  5 Example 15: Terbinafine HCl 75%(W/W) Polyethylene Glycol 4000 20 Polyvinylpyrrolidone  5

[0066] Non pH Sensitive Delayed Release Component

[0067] Formulate the composition by mixing the ingredients in a suitablepharmaceutical mixer or granulator such as a planetary mixer, high-sheargranulator, fluid bed granulator, or extruder, in the presence of wateror other solvent, or in a hot melt process. If water or other solventwas used, dry the blend in a suitable pharmaceutical drier, such as avacuum oven or forced-air oven. Allow the product to cool, the productmay be sieved or granulated, and compressed using a suitable tabletpress, such as a rotary tablet press. Ingredient Conc. (% W/W) Example16: Fluconazole 65% (W/W) Microcrystalline cellulose 20 Polyox 10Croscarmellose sodium  5 Example 17: Fluconazole 55% (W/W)Microcrystalline cellulose 25 Polyox 10 Glyceryl monooleate 10 Example18: Fluconazole 65% (W/W) Polyox 20 Hydroxypropylcellulose 10Croscarmellose sodium  5 Example 19: Fluconazole 75% (W/W) Polyethyleneglycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D  5 Example20: Fluconazole 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose  5Example 21: Ketoconazole 70% (W/W) Polyox 20 Hydroxypropylcellulose  5Croscarmellose sodium  5 Example 22: Ketoconazole 75% (W/W) Polyox 15Hydroxypropylcellulose  5 Ethylcellulose  5 Example 23: Ketoconazole 75%(W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 EudragitRL 30D  5 Example 24: Ketoconazole 80% (W/W) Polyethylene glycol 8000 10Polyvinylpyrrolidone  5 Eudgragit R 30D  5 Example 25: Griseofulvin 65%(W/W) Polyethylene glycol 4000 20 Hydroxypropylcellulose 10 Eudragit RL30D  5 Example 26: Griseofulvin 75% (W/W) Microcrystalline cellulose 15Hydroxypropylcellulose  5 Ethylcellulose  5 Example 27: Griseofulvin 80%(W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000  5 EudgragitRL 30D  5 Example 28: Griseofulvin 75% (W/W) Polyethylene glycol 8000 20Ethylcellulose  5 Example 29: Terbinafine HCl 75% (W/W) Polyethyleneglycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D  5 Example30: Terbinafine HCl 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose 5

[0068] Enteric Release Component

[0069] Formulate the ingredients by mixing the ingredients in a suitablepharmaceutical mixer or granulator such as a planetary mixer, high-sheargranulator, fluid bed granulator, or extruder, in the presence of wateror other solvent, or in a hot melt process. If water or other solventwas used, dry the blend in a suitable pharmaceutical drier, such as avacuum oven or forced-air oven. Allow the product to cool, the productmay be sieved or granulated, and compressed using a suitable tabletpress, such as a rotary tablet press. Ingredient Conc. (% W/W) Example31: Fluconazole 65% (W/W) Microcrystalline cellulose 20 CelluloseAcetate Pthalate 15 Example 32: Fluconazole 55% (W/W) Microcrystallinecellulose 25 Cellulose Acetate Pthalate 10 Hydroxypropylmethylcellulose10 Example 33: Fluconazole 65% (W/W) Polyox 20 Hydroxypropylcellulosepthalate 10 Eudragit L30D  5 Example 34: Fluconazole 75% (W/W)Polyethylene glycol 2000 10 Eudragit L 30D 10 Eudragit RL 30D  5 Example35: Fluconazole 40% (W/W) Microcrystalline Cellulose 40 CelluloseAcetate Pthalate 10 Example 36: Ketoconazole 70% (W/W)Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10 Example 37:Ketoconazole 70% (W/W) Eudragit L 30D 15 Hydroxypropylcellulose 10Ethylcellulose  5 Example 38: Ketoconazole 75% (W/W) Polyethylene glycol2000 10 Eudragit L 30D 15 Example 39: Ketoconazole 40% (W/W) Lactose 50Eudgragit L 30D 10 Example 40: Griseofulvin 65% (W/W) MicrocrystallineCellulose 20 Eudragit L 30D 10 Example 41: Griseofulvin 75% (W/W)Microcrystalline Cellulose 15 Hydroxypropylcellulose pthalate 10 Example42: Griseofulvin 80%(W/W) Lactose 10 Eudragit L 30D 10 Example 43:Griseofulvin 70% (W/W) Polyethylene glycol 4000 20 Cellulose acetatepthalate 10 Example 44: Terbinafine HCl 60% (W/W) Polyethylene glycol2000 10 Lactose 20 Eudragit L 30D 10 Example 45: Terbinafine HCl 70%(W/W) Microcrystalline cellulose 20 Cellulose acetate pthalate 10

[0070] Sustained Release Component

[0071] Formulate the composition by mixing the ingredients in a suitablepharmaceutical mixer or granulator such as a planetary mixer, high-sheargranulator, fluid bed granulator, or extruder, in the presence of wateror other solvent, or in a hot melt process. If water or other solventwas used, dry the blend in a suitable pharmaceutical drier, such as avacuum oven or forced-air oven. Allow the product to cool, the productmay be sieved or granulated, and compressed using a suitable tabletpress, such as a rotary tablet press. Ingredient Conc. % W/W) Example46: Fluconazole 65% (W/W) Ethylcellulose 20 Polyox 10Hydroxypropylmethylcellulose  5 Example 47: Fluconazole 55% (W/W)Lactose 25 Polyox 10 Glyceryl monooleate 10 Example 48: Fluconazole 70%(W/W) Polyox 20 Hydroxypropylcellulose 10 Example 49: Ketoconazole 75%(W/W) Lactose 15 Hydroxypropylcellulose  5 Ethylcellulose  5 Example 50:Ketoconazole 75% (W/W) Polyethylene glycol 4000 10 Lactose 10 EudragitRL 30D  5 Example 51: Ketoconazole 80% (W/W) Polyethylene glycol 8000 10Hydroxypropylmethylcellulose  5 Eudgragit RS 30D  5 Example 52:Griseofulvin 75% (W/W) Hydroxyethylcellulose 10 Polyethylene glycol 400010 Hydroxypropylcellulose  5 Example 53: Griseofulvin 75% (W/W) Lactose10 Povidone (PVP) 10 Polyethylene glycol 2000  5 Example 54: TerbinafineHCl 75% (W/W) Polyethylene glycol 4000 10 Povidone (PVP) 10Hydroxypropylcellulose  5 Example 55: Terbinafine HCl 75% (W/W) Lactose15 Polyethylene glycol 4000  5 Polyvinylpyrrolidone  5 Example 56:Ketoconazole 40% (W/W) Eudragit S100 50 Triethyl Citrate 10 Example 57:Ketoconazole 50% (W/W) Sureteric 50 Example 58: Ketoconazole 50% (W/W)Eudragit S100 45 Triethyl Citrate  5

[0072] Three Pulses

EXAMPLE 59

[0073] 1. Antifungal Matrix Pellet Formulation and Preparation Procedure(Immediate Release)

[0074] A. Pellet Formulation

[0075] The composition of the antifungal matrix pellets provided inTable 1. TABLE 1 Composition of Antifungal Pellets Component Percentage(%) Antifungal 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 PurifiedWater Total 100 

[0076] B. Preparation Procedure for antifungal Matrix Pellets

[0077] 1.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupehigh shear granulator.

[0078] 1.2.2 Add 20% Povidone K29/32 binder solution slowly into thepowder blend under continuous mixing.

[0079] 1.2.3 Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.0 mm.

[0080] 1.2.4 Spheronize the extrudate using a Model SPH20 CalevaSpheronizer.

[0081] 1.2.5 Dry the spheronized pellets at 50° C. overnight.

[0082] 1.2.6 Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0083] The above procedure is used to make pellets of a first antifungaland pellets of a second different antifungal.

[0084] 1.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0085] A. Dispersion Formulation

[0086] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the antifungal matrix pellets is provided below in Table 2.TABLE 2 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 55.0 Triethyl Citrate 1.6 Talc 8.0Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9

[0087] B. Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0088] 1.3.1 Suspend triethyl citrate and talc in deionized water.

[0089] 1.3.2 The TEC/talc suspension is then homogenized using aPowerGen 700 high shear mixer.

[0090] 1.3.3 Add the TEC/talc suspension slowly to the Eudragit® L 30D-55 latex dispersion while stirring.

[0091] 1.3.4 Allow the coating dispersion to stir for one hour prior toapplication onto the antifungal matrix pellets.

[0092] 1.4 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0093] A. Dispersion Formulation

[0094] The composition of the aqueous Eudragit® S 100 dispersion appliedto the antifungal matrix pellets is provided below in Table 3. TABLE 3Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%)Part A Eudragit ® S 100 12.0 1 N Ammonium Hydroxide 6.1 Triethyl Citrate6.0 Purified Water 65.9 Part B Talc 2.0 Purified Water 8.0 Solid Content20.0 Polymer Content 12.0

[0095] B. Preparation Procedure for an Eudragit® S 100 AqueousDispersion

[0096] Part I:

[0097] (i) Dispense Eudragit® S 100 powder in deionized water withstirring.

[0098] (ii) Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0099] (iii) Allow the partially neutralized dispersion to stir for 60minutes.

[0100] (iv) Add triethyl citrate drop-wise into the dispersion withstirring. Stir for about 2 hours prior to the addition of Part B.

[0101] Part II:

[0102] (i) Disperse talc in the required amount of water

[0103] (ii) Homogenize the dispersion using a PowerGen 700D high shearmixer.

[0104] (iii) Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0105] 1.5 Coating Conditions for the Application of Aqueous CoatingDispersions

[0106] The following coating parameters are used to coat matrix pelletswith each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous filmcoating. STREA 1 ™ Table Top Laboratory Coating Equipment Fluid BedCoater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet AirTemperature 40 to 45° C. Outlet Air Temperature 30 to 33° C. AtomizationAir Pressure 1.8 Bar Pump Rate 2 gram per minute

[0107] (i) Coat matrix pellets with L30 D-55 dispersion such that youapply 12% coat weight gain to the pellets.

[0108] (ii) Coat matrix pellets with S100 dispersion such that you apply20% coat weight gain to the pellets.

[0109] 1.6 Encapsulation of the Antifungal Pellets

[0110] Pellets are filled into size 00 hard gelatin capsules at a ratioof 30%: 30%: 40%: Immediate-release matrix pellets uncoated, L30 D-55coated pellets and S100 coated pellets respectively. The capsule isfilled with the three different pellets to achieve a the desire dosage.

[0111] The immediate release matrix pellets include the firstantifungal, the L30 D-55 coated pellets are made by coating matrixpellets that contain the second antifungal and the S100 coated pelletsare made by coating matrix pellets that contain the first antifungal.

[0112] Three Pulses

EXAMPLE 60.

[0113] Antifungal Pellet Formulation and Preparation Procedure

[0114] 60.1 Pellet Formulations for subsequent coating

[0115] The composition of the Antifungaltrihydrate matrix pelletsprovided in Table 4. TABLE 4 Composition of AntifungalMatrix PelletsComponent Percentage (%) AntifungalTrihydrate powder 92 Avicel PH 1017.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100

[0116] 60.2 Preparation Procedure for AntifingalMatrix Pellets

[0117] 60.2.1 Blend Antifungaland Avicel® PH 101 using a low shearblender.

[0118] 60.2.2 Add the hydroxypropyl methylcellulose binder solutionslowly into the powder blend under continuous mixing.

[0119] 60.2.3 Extrude the wet mass using an LCI Bench Top Granulator.The diameter of the screen of the Bench Top Granulator is 0.8 mm.

[0120] 60.2.4 Spheronize the extrudate using a QJ-230 Spheronizer usinga small cross section plate.

[0121] 60.2.5 Dry the spheronized pellets at 60° C. using a fluid beddryer until the exhaust temperature reaches 40° C.

[0122] 60.2.6 Pellets between 20 and 40 Mesh were collected for furtherprocessing.

[0123] 60.2.7 The above procedure is used to produce pellets thatcontain a first antifungal and pellets that contain a second anddifferent antifungal.

[0124] 60.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0125] 60.3.1 Dispersion Formulation

[0126] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the Antifulngalmatrix pellets is provided below in Table 5.TABLE 5 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 41.6 Triethyl Citrate 2.5 Talc 5.0Purified Water 50.9 Solids Content 20.0 Polymer Content 12.5

[0127]60.4 Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0128] 60.4.1 Suspend triethyl citrate and talc in deionized water.

[0129] 60.4.2 The TEC/talc suspension is mixed using laboratory mixer.

[0130] 60.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L30 D-55 latex dispersion while stirring.

[0131] 60.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the Antifingalmatrix pellets.

[0132] 60.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0133] 60.5.1 Dispersion Formulation

[0134] The composition of the aqueous Eudragit® S 100 dispersion appliedto the Antifungalmatrix pellets is provided below in Table 6. TABLE 6Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%)Part A Eudragit ® S 100 10.0 1 N Ammonium Hydroxide 5.1 Triethyl Citrate5.0 Water 64.9 Part B Talc 5.0 Water 10.0 Solid Content 25.0 PolymerContent 10.0

[0135]60.6 Preparation Procedure for an Eudragit® S 100 AqueousDispersion

[0136] Part A:

[0137] 60.6.1 Dispense Eudragit® S 100 powder in deionized water withstirring.

[0138] 60.6.2 Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0139] 60.6.3 Allow the partially neutralized dispersion to stir for 60minutes.

[0140] 60.6.4 Add triethyl citrate drop-wise into the dispersion withstirring and let stir overnight prior to the addition of Part B.

[0141] Part B:

[0142] 60.6.5 Disperse talc in the required amount of water

[0143] 60.6.6 Stir the dispersion using an overhead laboratory mixer.

[0144] 60.6.7 Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0145] 60.7 Coating Conditions for the Application of Aqueous CoatingDispersions

[0146] The following coating parameters are used for both the Eudragit®L 30 D-55 and Eudragit® S 100 aqueous film coating processes. CoatingEquipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzlediameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40 to 45°C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure 1.8 BarPump Rate 2-6 gram per minute

[0147] 60.7.1 Coat matrix pellets with L30 D-55 dispersion such that youapply 20% coat weight gain to the pellets.

[0148] 60.7.2 Coat matrix pellets with S100 dispersion such that youapply 37% coat weight gain to the pellets.

[0149] 60.8 Preparation of AntifungalGranulation (Immediate ReleaseComponent) for tabletting TABLE 7 Composition of AntifungalGranulationComponent Percentage (%) AntifungalTrihydrate powder 92 Avicel PH 1017.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100

[0150] 60.8.1 Blend Antifungaland Avicel® PH 101 using a low shearblender.

[0151] 60.8.2 Add the hydroxypropyl methylcellulose binder solutionslowly into the powder blend under continuous mixing.

[0152] 60.8.3 Dry the granulation at 60° C. using a fluid bed dryeruntil the exhaust temperature reaches 40° C.

[0153] 60.8.4 Granules between 20 and 40 Mesh are collected for furtherprocessing.

[0154] 60.9 Tabletting of the AntifungalPellets TABLE 8 Composition ofAntifungalTablets Component Percentage (%) First antifungalgranules 32.5Avicel PH 200 5.0 Second antifungalL30D-55 coated pellets 30 FirstantifungalS100 coated pellets 30 Colloidal silicon dioxide 1.5 Magnesiumstearate 1.0 Total 100

[0155] 60.9.1 Blend the Antifungalgranules, Avicel PH-200,Antifungalpellets and colloidal silicon dioxide for 15 minutes in atumble blender.

[0156] 60.9.2 Add the magnesium stearate to the blender, and blend for 5minutes.

[0157] 60.9.3 Compress the blend on a rotary tablet press.

[0158] 60.9.4 The fill weight should be adjusted to achieve the desireddosage.

[0159] Four pulses

EXAMPLE 61

[0160] 1 Antifungal Matrix Pellet Formulation and Preparation Procedure

[0161] 61.1 Pellet Formulation

[0162] The composition of the antifungal matrix pellets provided inTable 9. TABLE 9 Composition of Antifungal Pellets Component Percentage(%) Antifungal 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 PurifiedWater Total 100 

[0163] 61.2 Preparation Procedure for Antifungal Matrix Pellets

[0164] 61.2.1 Blend antifingal and Avicel® PH 101 using a Robot Coupehigh shear granulator.

[0165] 61.2.2 Add 20% Povidone K29/32 binder solution slowly into thepowder blend under continuous mixing.

[0166] 61.2.3 Extrude the wet mass using an LCI Bench Top Granulator.The diameter of the screen of the Bench Top Granulator was 1.0 mm.

[0167] 61.2.4 Spheronize the extrudate using a Model SPH20 CalevaSpheronizer.

[0168] 61.2.5 Dry the spheronized pellets at 50° C. overnight.

[0169] 61.2.6 Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0170] 61.2.7 The above procedure is used to prepare pellets thatcontain a first antifungal and pellets that contain a second antifungal.

[0171] 61.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0172] 61.3.1 Dispersion Formulation

[0173] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the antifingal matrix pellets is provided below in Table 10.TABLE 10 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 55.0 Triethyl Citrate 1.6 Talc 8.0Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9

[0174]61.4 Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0175] 61.4.1 Suspend triethyl citrate and talc in deionized water.

[0176] 61.4.2 The TEC/talc suspension is then homogenized using aPowerGen 700 high shear mixer.

[0177] 61.4.3 Add the TEC/talc suspension slowly to the Eudragit® L 30D-55 latex dispersion while stirring.

[0178] 61.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the antifungal matrix pellets.

[0179] 61.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0180] 61.5.1 Dispersion Formulation

[0181] The composition of the aqueous Eudragit® S 100 dispersion appliedto the antifungal matrix pellets is provided below in Table 11. TABLE 11Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%)Part A Eudragit ® S 100 12.0 1 N Ammonium Hydroxide 6.1 Triethyl Citrate6.0 Purified Water 65.9 Part B Talc 2.0 Purified Water 8.0 Solid Content20.0 Polymer Content 12.0

[0182]61.6 Preparation Procedure for an Eudragit® S 100 AqueousDispersion

[0183] Part A:

[0184] 61.6.1 Dispense Eudragit® S 100 powder in deionized water withstirring.

[0185] 61.6.2 Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0186] 61.6.3 Allow the partially neutralized dispersion to stir for 60minutes.

[0187] 61.6.4 Add triethyl citrate drop-wise into the dispersion withstirring. Stir for about 2 hours prior to the addition of Part B.

[0188] Part B:

[0189] 61.6.5 Disperse talc in the required amount of water

[0190] 61.6.6 Homogenize the dispersion using a PowerGen 700D high shearmixer.

[0191] 61.6.7 Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0192] 61.7 Coating Conditions for the Application of Aqueous CoatingDispersions

[0193] The following coating parameters are used for coating with eachof the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure1.8 Bar Pump Rate 2 gram per minute

[0194] 61.7.1 Coat matrix pellets with L30 D-55 dispersion such that youapply 12% coat weight gain to the pellets.

[0195] 61.7.2 Coat matrix pellets with L30 D-55 dispersion such that youapply 30% coat weight gain to the pellets.

[0196] 61.7.3 Coat matrix pellets with S 100 dispersion such that youapply 20% coat weight gain to the pellets.

[0197] 61.8 Encapsulation of the Antifungal Pellets

[0198] Pellets are filled into size 00 hard gelatin capsules at a ratioof 20%:30%:20%:30% Immediate-release matrix pellets (uncoated), L30 D-55coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gainand S100 coated pellets respectively.

[0199] The capsule is filled with the four different pellets to achievethe desired dosage.

[0200] The immediate release pellets contain the first antifungal; theL30 D-55 12% weight gain coated pellets containe the second antifungal;the L30 D-55 30% weight gain coated pellets contain the first antifungaland the S100 coated pellets contain the second antifungal.

[0201] The present invention is advantageous in that a synergisticanti-fungal will be dosed in an alternate pulse to another, synergisticanti-fungal. This will alternate the exposure to the fungus in such away as to make both anti-fungals more effective than if they wereco-administered.

[0202] Numerous modifications and variations of the present inventionare possible in light of the above teachings; therefore, within thescope of the appended claims, the invention may be practiced otherwisethan as particularly described.

What is claimed is:
 1. An anti-fungal product comprising: at least threedosage forms, each dosage form comprising an anti-fungal and apharmaceutically acceptable carrier, one of said dosage forms includingat least a first anti-fungal and a second of said dosage forms includingat least a second anti-fungal that is different than the firstanti-fungal.
 2. The product of claim 1 wherein each of the dosage formshas a different release profile.
 3. The product of claim 1 wherein thefirst dosage form is an immediate release dosage form.
 4. The product ofclaim 3 wherein the second and third dosage forms are delayed releasedosage forms.
 5. The product of claim 4 wherein anti-fungal releasedfrom the second dosage form reaches a C_(max) in serum after anti-fungalreleased from the first dosage form reaches C_(max) in serum.
 6. Theproduct of claim 5 wherein anti-fungal released from the third dosageform reaches C_(max) in serum after anti-fungal released from the seconddosage form reaches C_(max) in serum.
 7. The product of claim 6 whereintotal anti-fungal released from the product reaches C_(max) in serumwithin twelve hours of administration.
 8. The product of claim 7 whereinthe product is a once a day product.
 9. The product of claim 1 whereineach of the three dosage forms includes at least the first and secondanti-fungal.
 10. The product of claim 1 wherein the first dosage formincludes the first anti-fungal, the second dosage form includes thefirst and second anti-fungal and the fourth dosage form includes thesecond anti-fungal.
 11. An anti-fungal product comprising: a first,second, third and fourth dosage form, said first dosage form comprisinga first anti-fungal and a pharmaceutically acceptable carrier; saidsecond dosage form comprising said first anti-fungal and apharmaceutically acceptable carrier; said third dosage form comprising asecond anti-fungal different from the first anti-fungal and apharmaceutically acceptable carrier; said fourth dosage form comprisingsaid second anti-fungal and a pharmaceutically acceptable carrier, saidsecond and third dosage forms having a release profile whereby themaximum serum concentration of the first anti-fungal and the secondanti-fungal released from the second and third dosage forms is reachedat a time later than the maximum serum concentration of the firstanti-fungal released from the first dosage form, and wherein the maximumserum concentration of the second anti-fungal released from the fourthdosage form reaches a maximum serum concentration at a time after themaximum serum concentration for the anti-fungal released from each ofthe first, second and third dosage forms is reached.
 12. The compositionof claim 1 wherein the first anti-fungal released from the second dosageform, and the second anti-fungal released from the third dosage formreach a maximum serum concentration at about the same time.
 13. Aprocess for treating a fungus infection in a host comprising:administering to the host the anti-fungal product of claim
 1. 14. Aprocess for treating a fungus infection in a host comprising:administering to the host the anti-fungal product of claim
 2. 15. Aprocess for treating a fungus infection in a host comprising:administering to the host the anti-fungal product of claim
 3. 16. Aprocess for treating a fungus infection in a host comprising:administering to the host the anti-fungal product of claim
 4. 17. Aprocess for treating a fungus infection in a host comprising:administering to the host the anti-fungal product of claim
 5. 18. Aprocess for treating a fungus infection in a host comprising:administering to the host the anti-fungal product of claim
 6. 19. Aprocess for treating a fungus infection in a host comprising:administering to the host the anti-fungal product of claim
 7. 20. Aprocess for treating a fungus infection in a host comprising:administering to the host the anti-fungal product of claim 8.